Project Summary This study seeks to estimate the effectiveness of newly FDA-approved extended- release naltrexone (XR-NTX) when initiated by opioid users leaving a larger urban jail. This study targets persons who have explicitly rejected methadone maintenance re-entry treatment, and are instead expected to leave jail out-of-treatment and at extraordinarily high risk for immediate opioid relapse and fatal accidental overdose, among other relapse-related adverse outcomes. XR-NTX in this case stands as an additional, `salvage' pharmacotherapy option among persons resistant to agonist medications, and we propose a randomized trial of XR-NTX versus enhanced `drug-free' treatment-as- usual to establish XR-NTX's effectiveness as re-entry relapse prevention. Further, an important question is also how XR-NTX would compare to jail methadone usual care, and this study will recruit an additional, non-randomized, quasi-experimental methadone cohort for comparative effectiveness purposes.